The primary objective of this proposal is to conduct a Phase 1/2 clinical trial as part of a development strategy for a new drug AT-101, in CLL. CLL is a rare disease with an annual incidence of 15,490, and a prevalence of about 60,000/year in the United States. It is an incurable cancer with limited therapeutic options. The median overall survival of patients with advance stage is approximately 3 years. Although CLL patients initially respond to combination chemotherapy regimen(s), eventually all relapse with fatal outcome. Development of new drugs for this cancer remains an important unmet need. B cell lymphoma-2 (Bcl-2) is an important antiapoptotic protein present in over 80% of CLL patients. It is associated with aggressive clinical course, resistance to therapy and compromised survival. At present there are no drugs approved for this target. The hypothesis proposed in this grant application focuses on the ability of a Bcl-2 agent, AT-101, to partner with the anti-CLL therapeutic lenalidomide, to thereby possibly increase the efficacy of the later. Preclinical work has demonstrated that lenalidomide mediates its antileukemic effect in CLL through activation of cell mediated immune response, which is compromised by Bcl-2, and that the therapeutic downregulation of Bcl-2 with AT-101 may augment immune directed killing. This Phase 2/3 clinical trial is proposed to determine the maximum tolerated dose (MTD), to determine the efficacy of the lenalidomide/AT-101 combination, and to test this hypothesis in CLL patients with relapsed disease.